Bacos et al. (1960) presented a family in which 9 members of 3 generations exhibited nodal rhythm with bradycardia and tended to develop paroxysms of atrial fibrillation in the fourth decade of life. Surawicz and Hariman (1988) provided ... Bacos et al. (1960) presented a family in which 9 members of 3 generations exhibited nodal rhythm with bradycardia and tended to develop paroxysms of atrial fibrillation in the fourth decade of life. Surawicz and Hariman (1988) provided a follow-up of this family. As predicted by Bacos et al. (1960), individuals in subsequent generations manifested slow heart rate with regular rhythm from birth and developed intermittent atrial fibrillation with established atrial fibrillation requiring chronic treatment later. Surawicz and Hariman (1988) found that some members of the third and fourth generations suffered from more symptomatic bradycardia at a younger age than their parents which led, in some cases, to pacemaker implantation. Sudden death, presumably of cardiac origin, had occurred in 1 member of the third generation. Lehmann and Klein (1978) reported a large family with sinus node dysfunction spanning 3 generations as an autosomal dominant trait. In some affected members, there was an association between the grade of mental retardation and the severity of the sinoatrial disorder. In another family, described in 140450, brachydactyly was combined. Mackintosh and Chamberlain (1979) described sinus node disease affecting both parents and both children in 1 family. Beyer et al. (1993) described a family in which a 10-year-old boy and his 20-year-old sister were found to have atrial fibrillation and bradyarrhythmia. Their father and grandfather, as well as their great-grandmother, had the same. This is clearly the same family as that reported later by Bertram et al. (1996). The 10-year-old proband had shown intrauterine and postnatal bradycardia, and atrial fibrillation was first documented electrocardiographically at 16 months of age. No structural heart defect was evident. A permanent ventricular demand pacemaker was implanted at the age of 10 years after syncope due to severe bradyarrhythmia. Idiopathic atrial fibrillation known since childhood was documented in 3 close relatives. A high-grade AV block resulting in bradyarrhythmia and the occurrence of ST-T changes in precordial leads could be demonstrated in all affected family members, suggesting a diffuse general conduction abnormality. Nof et al. (2007) studied 8 affected and 8 unaffected members of a 4-generation family with asymptomatic sinus bradycardia. Affected individuals had an average heart rate of less than 55 bpm on 24-hour ECG with a minimum of less than 36 bpm, whereas unaffected individuals had an average heart rate greater than 63 bpm and a minimum rate greater than 49 bpm. Exercise testing demonstrated normal chronotropic and exercise capacity, and all had a normally structured heart on echocardiography. There was no history of dizziness, syncope, or sudden cardiac death in the family. Electrophysiologic testing of 2 affected family members confirmed significant sinus node dysfunction, with prolonged average and corrected sinus node recovery times.
In a 66-year-old woman with marked sinus bradycardia (41 bpm) and intermittent atrial fibrillation who suffered a severe syncopal episode, Schulze-Bahr et al. (2003) identified heterozygosity for a 1-bp deletion (605206.0002) in the pacemaker channel gene HCN4. Family ... In a 66-year-old woman with marked sinus bradycardia (41 bpm) and intermittent atrial fibrillation who suffered a severe syncopal episode, Schulze-Bahr et al. (2003) identified heterozygosity for a 1-bp deletion (605206.0002) in the pacemaker channel gene HCN4. Family history was unremarkable, and the mutation was not found in her 3 unaffected children or in 362 control chromosomes. In a 43-year-old woman with syncope and a 24-hour ECG showing severe bradycardia (39 bpm on average), cardiac arrest for 40 seconds followed by polymorphic ventricular tachycardia and torsade de pointes, Ueda et al. (2004) identified heterozygosity for a mutation (D553N; 605206.0003) in the HCN4 gene. The patient's resting ECG showed flat T waves and a QTc of 670 ms. The mutation was also found in her affected sister and son, but was not present in 380 control chromosomes. Milanesi et al. (2006) screened the HCN4 gene in 52 patients with bradycardia and identified a mutation (S672R; 605206.0001) in affected members of a 3-generation Italian family with asymptomatic sinus bradycardia. In 8 affected members of a 4-generation family with asymptomatic sinus bradycardia, Nof et al. (2007) identified a heterozygous mutation in the HCN4 gene (G480R; 605206.0004). The mutation was not found in 8 unaffected family members or 100 unrelated control chromosomes.